JP2003119177A - Method for producing condensed aromatic compound and production intermediate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a 1,2-acid anhydride condensed aromatic compound or a 1,2-acid imide condensed aromatic compound useful as a production intermediate for medicines, agrochemcials or a plurality of general-purpose chemicals and a method for producing the same. SOLUTION: This method for producing the compound represented by general formula (II) [R<1> and R<2> are each the same or different and denote each hydrogen atom or a substituent; ring A denotes an aromatic homo- or a heterocyclic ring which may be substituted; and T' denotes oxygen atom or a group represented by the formula N-R (R denotes hydrogen atom or a substituent)] or its salt is carried out as follows. A compound represented by general formula (I) T denotes oxygen atom or a group represented by the formula N-R [R has the same meaning as described in general formula (II)]; and R<1> , R<2> and ring A have each the same meaning as described in general formula (II)} or its salt is subjected to dehydrogenating reaction in the presence of (1) a transition metal catalyst or (2) a base.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a 1,2-acid anhydride condensed aromatic compound or 1,2-acid imide condensed aromatic compound useful as an intermediate for the production of pharmaceuticals, agricultural chemicals, and many general-purpose chemicals. And a production intermediate thereof.
Specifically, aromatic cyclization by dehydrogenation under extremely mild conditions, useful as a production intermediate for various general-purpose products 1,2-acid anhydride condensed aromatic compound or 1,2-acid imide condensed aromatic compound Relates to a method of manufacturing the.

[0002]

2. Description of the Related Art There have been some reports on the aromatic cyclization technology by dehydrogenation (Chemical Reviews (Chem. Rev.), Vol. 78, p. 317, 1978). For example, sulfur, group 16 elements such as selenium, metals such as platinum and palladium, aluminum chloride, Lewis acids such as antimony chloride, chloranil, quinone reagents such as 2,3-dichloro-5,6-dicyanobenzoquinone, tetrafluoroboric acid It is known to perform a dehydrogenation reaction using a trityl salt such as triphenylcarbenium or triphenylcarbenium trifluoroacetate, or a radical agent such as diphenylpicrylhydrazyl.

On the other hand, 1,2-acid anhydride condensed aromatic compounds or 1,2-acid imide condensed aromatic compounds are used for drugs, agricultural chemicals,
There are many useful intermediates for the production of many general-purpose chemicals, and various methods are known as the production methods. For example, there are two known methods for producing a 1,2-naphthalene anhydride derivative. That is, Journal of the American Chemical Society (J. Am. Chem. Soc.), Vol. 58, p. 2314, 1936.
According to the year, γ-phenylbutyric acid derivatives (3-methoxy, 4-
(Methoxy, 3-methoxy-4-methyl) was reacted with diethyl oxalate and potassium ethoxide to give ethyl 3-carboethoxy-2-oxo-5-phenylpentanoate derivative and then with 80% sulfuric acid. The ring is closed to give a 3,4-dihydronaphthalene-1,2-anhydride derivative. At this time, some dehydrogenation occurs and the 1,2-naphthalene anhydride derivative is mixed in.
A method of synthesizing 1,2-naphthalene anhydride by heating at 0 ° C is disclosed. Also, Journal of Organic Chemistry (J. Org. Chem.), Volume 41, 3925.
Pp. 1976, dibromostyrene was converted to α-bromostyrene using sodium hydroxide and a phase transfer catalyst and then refluxed in maleic anhydride and xylene to give 1,2-
Dihydronaphthalene-1,2-anhydride is obtained. A method of synthesizing 1,2-naphthalenic anhydride by adding sulfur to this and heating at 250 ° C. is disclosed. Further, for example, a 1,2-naphthalenedicarboxylic acid derivative may be reacted with acetic anhydride to give a 1,2-naphthalene anhydride derivative. A method for producing a 1,2-naphthalenedicarboxylic acid derivative is described in Przem. Chem., Vol. 51, p. 227, 1
According to 972, after 2-methylnaphthalene was chloromethylated to lead to 1-chloromethyl-2-methylnaphthalene, it was heated to 240 ° C under pressure with sodium dichromate to give 1,2-naphthalenedicarboxylic acid. A method of synthesizing an acid derivative is disclosed.

[0004]

As described above, the known
In any of the methods for producing a 1,2-acid anhydride condensed aromatic compound or a 1,2-acid imide condensed aromatic compound, the reaction temperature is 240-25.
Since the temperature is as high as 0 ° C and side reactions and decomposition occur depending on the substrate, industrial application is difficult. Further, the catalysts and reagents themselves used are expensive, and when a naphthalene skeleton is used as a raw material, there are problems that the available naphthalene compounds are few and expensive.

The present inventors have conducted extensive studies to solve these problems, and as a result, 1) a transition metal catalyst or 2)
When a dehydrogenation reaction is carried out under extremely mild and safe conditions using a base, surprisingly, a 1,2-naphthalene anhydride compound or a 1,2-naphthalene imide compound can be produced, and 3,4- By reacting a dihydronaphthalene-1,2-acid anhydride compound with an amine compound, it was unexpectedly found that an aromatic cyclized 1,2-naphthalene imide compound could be produced in one step, and based on these, The present invention has been completed.

[0006]

That is, the present invention is (1) General formula (I)

[Chemical 14]

[Wherein T is an oxygen atom or a formula NR (wherein
R represents a hydrogen atom or a substituent. ), R ¹ and R ² are the same or different and each represent a hydrogen atom or a substituent, and ring A represents an optionally substituted aromatic homolog or heterocycle. ] The compound or salt thereof represented by the general formula (II), which is subjected to a dehydrogenation reaction in the presence of 1) a transition metal catalyst or 2) a base.

[Chemical 15]

[Wherein each symbol has the same meaning as defined above,
T'represents an oxygen atom or a group represented by the formula NR (wherein R represents a hydrogen atom or a substituent). ] The manufacturing method of the compound or its salt represented by these; (2) A transition metal catalyst is a 0 value palladium catalyst or 0.
(3) The production method according to (1), which is a valent platinum catalyst; (3) The production method according to (2), in which a 0-valent palladium catalyst or a 0-valent platinum catalyst is a catalyst supported on a solid carrier;

(4) The base is one base selected from 1) alkali metal hydrides, 2) inorganic hydroxides, 3) metal alkoxides having 1 to 6 carbon atoms, and 4) amines or salts thereof ( 1) The production method described above; (5) The amine is an aliphatic amine; (4) The production method described above;
~ 200 times mol is used, (5) The production method described in (5) General formula (V)

[Chemical 16]

[In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom or a substituent, and Ring A represents an optionally substituted aromatic homolog or heterocycle. ] The compound or its salt represented by these, and general formula (VI)

[Chemical 17] [In the formula, R represents a hydrogen atom or a substituent. ] The general formula (VII) characterized by reacting with an amine compound represented by

[Chemical 18]

[In the formula, each symbol has the same meaning as described above. ]
(8) A method for producing a compound represented by: or (8) a reaction at about 0 ° C to about 200 ° C (1) to (7), (9) as a solvent Use acetic acid (1) to (7)
(1) The molar ratio of amine to acetic acid in the solvent (acetic acid /
(Amine) is 0.01 to 6;

(11) General formula (III)

[Chemical 19]

[Wherein T is an oxygen atom or a formula NR (wherein
R represents a hydrogen atom or a substituent. ), R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or a substituent. ] Or a salt thereof is subjected to a dehydrogenation reaction in the presence of 1) a transition metal catalyst or 2) a base to give a compound represented by the general formula (IV):

[Chemical 20]

[Wherein each symbol has the same meaning as defined above,
T'represents an oxygen atom or a group represented by the formula NR (wherein R represents a hydrogen atom or a substituent). ] The manufacturing method as described in (1) which obtains the compound or its salt represented by these; (12) General formula (VIII)

[Chemical 21]

[In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or a substituent. ] The compound or its salt represented by these, and general formula (VI)

[Chemical formula 22] [In the formula, R represents a hydrogen atom or a substituent. ] By reacting with an amine compound or a salt thereof represented by the general formula (IX)

[Chemical formula 23]

[In the formula, each symbol has the same meaning as described above. ]
(7) The production method according to (7) for obtaining a compound represented by: or a salt thereof; (13) R ¹ , R ² , R ³ , R ⁴ and R ⁶ are hydrogen atoms, R ⁵ is a halogen atom, The production method according to (11) or (12), wherein R is a C _1-6 alkyl group; (14) General formula (X)

[Chemical formula 24]

[Wherein T is an oxygen atom or a formula NR (wherein
R represents a hydrogen atom or a substituent. ), R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or a substituent. However, at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is a halogen atom. ] The compound or its salt represented by these; (15) General formula (XI)

[Chemical 25]

[Wherein T is an oxygen atom or a formula NR (wherein
R represents a hydrogen atom or a substituent. ), R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or a substituent. However, at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is a halogen atom. ] Or a salt thereof; (16) (14) or (1) in which R ⁵ is a halogen atom
(17) The compound according to (16), wherein R ¹ , R ² , R ³ , R ⁴ and R ⁶ are hydrogen atoms and R is a C _1-6 alkyl group; ) Formula (XII)

[Chemical formula 26] For producing a compound having a partial structure represented by (1
5) Use of the described compound;

The contents of the present invention will be described in detail below. Well
First, the terms used in the present invention will be explained. Ring A
Is an optionally substituted aromatic homocycle or substituted
The aromatic heterocycle which may be present is shown. "Substitution" represented by ring A
Aromatic homocycle or heterocycle which may be
The elementary or heterocyclic ring may be, for example, a monocyclic or condensed polycyclic ring.
Cyclic aromatic carbocycle, or monocyclic or fused polycyclic aromatic ring
Aromatic heterocycles can be used. Preferably C _6-14Good luck
Aromatic carbocycle (aryl) or 5- to 14-membered aromatic hetero
Rings (heteroaryl) can be used and are more preferred
Kuha C_6-10Aromatic carbocycle (aryl) or 5 to 10
Membered aromatic heterocycle (heteroaryl), more preferred
It is C₆Aromatic carbocycle (aryl) or 5 to 6 members
It is an aromatic heterocycle. "Aromatic allotrope
Specific examples of the "ring" include, for example, pentazole;
Benzene, naphthalene, anthracene, azulene, fe
Nantren, Phenalene, Fluorene, Indacene, Bi
C such as phenylene, heptalen, acenaphthylene_6-14A
A reel group or the like is preferable, and among them, benzene, naphthalene,
Anthracene and the like are particularly preferable. "Aromatic heterocycle"
Is, for example, as an atom (ring atom) constituting a ring system, an acid
Hetero atom selected from elementary atom, sulfur atom, nitrogen atom, etc.
Fewer 1 to 3 (preferably 1 to 2) atoms
And 1 (preferably 1 to 4 and more preferably 1 to 4)
Aromatic heterocycles including 1 to 2) can be used.
It

Specific examples of the "aromatic heterocycle" include furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole,
Imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazan, 1,2,3-thiadiazole, 1,
2,4-thiadiazole, 1,3,4-thiadiazole,
5- to 6-membered monocyclic aromatic heterocycles such as 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, and benzofuran, isobenzofuran, benzo [ B ] thiophene, indoline, isoindoline,
1H-indazole, benzindazole, benzoxazole, 1,2-benzisoxazole, benzothiazole, benzopyran, 1,2-benzisothiazole, 1H-benzotriazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine, Purine, buteridine, carbazole, α-carboline, β-carboline, γ-carboline, acridine, phenoxazine, phenothiazine, phenazine, phenoxatin, thianthrene, phenatridine, phenatroline, indolizine, pyrrolo [1,2
- b] pyridazine, pyrazolo [1,5- a] pyridine,
Imidazo [1,2- a ] pyridine, imidazo [1,5-
a ] pyridine, imidazo [1,2- b ] pyridazine, imidazo [1,2- a ] pyrimidine, 1,2,4-triazolo [4,3- a ] pyridine, 1,2,4-triazolo [4,
3- b] can be used 8-12 membered fused polycyclic aromatic heterocyclic rings such as pyridazine. Preferably 5 to 6
Membered monocyclic aromatic heterocycles can be used.

Here, the substituent of the "optionally substituted aromatic homocycle or heterocycle" may be protected by a conventional method of organic chemical synthesis, if necessary, and does not affect the reaction. Unless otherwise specified, for example, (i) an optionally substituted alkyl group, (ii) an optionally substituted alkenyl group, (iii) an optionally substituted alkynyl group, (iv) substituted Optionally substituted aryl group, (v) optionally substituted aralkyl group, (vi) optionally substituted cycloalkyl group, (vii) optionally substituted cycloalkenyl group, (viii) substituted Optionally substituted heterocyclic group, (ix) optionally substituted amino group, (x) optionally substituted imidoyl group (for example, formula —C (U ′) =
N-U [in the formula, U and U ′ each represent a hydrogen atom or a substituent (U preferably represents a hydrogen atom)], etc.), (xi) an optionally substituted amidino group (For example, the formula −C (NT′T ″) = N−T [where T,
T ′ and T ″ each represent a hydrogen atom or a substituent (T is preferably a hydrogen atom)], (xii) optionally substituted hydroxyl group, (xiii) substituted Optionally thiol group, (xiv) optionally substituted alkylsulfinyl group, (xv) esterified or amidated carboxyl group, (xvi) optionally substituted thiocarbamoyl group, ( xvii) optionally substituted sulfamoyl group, (xviii) halogen atom (eg, fluorine, chlorine, bromine, iodine etc., preferably chlorine, bromine etc.), (xix) cyano group, (xx) isocyano group, (xx
i) cyanate group, (xxii) isocyanate group, (xxiii) thiocyanate group, (xxiv) isothiocyanate group, (xxv)
Nitro group, (xxvi) nitroso group, (xxvii) sulfonic acid-derived acyl group, (xxviii) carboxylic acid-derived acyl group, (xxi
x) an oxo group or the like is used, and these optional substituents are 1 to 5 (preferably 1 to 3) at substitutable positions.
It may be replaced.

As the substituent, “may be substituted”
Examples of the alkyl group in the “alkyl group” include
Chill, ethyl, n-propyl, isopropyl, n-butyl
, Isobutyl, sec-butyl, tert-butyl, n-pe
Methyl, isopentyl, neopentyl, 1-methylpro
Pill, n-hexyl, isohexyl, 1,1-dimethyl
Butyl, 2,2-dimethylbutyl, 3,3-dimethylbuty
C such as 3,3 dimethylpropyl_1-6For alkyl etc.
Can be Here, as a substituent of the alkyl group
Is a lower alkoxy group (eg, methoxy, ethoxy, pro
C such as poxy _1-6Alkoxy, etc.), halogen atom (eg,
Fluorine, chlorine, bromine, iodine, etc.), lower alkyl group
(Eg C such as methyl, ethyl, propyl, etc._1-6Alkyl
Etc.), lower alkenyl groups (eg, C such as vinyl and allyl)
_2-6Alkenyl, etc., lower alkynyl group (eg, ethini)
C such as Le and Propargil_2-6Alkynyl, etc.), substituted
Optionally an amino group, an optionally substituted hydroxyl group,
Cyano group, optionally substituted amidino group, carboxy
Si group, lower alkoxycarbonyl group (eg, methoxycarl
C such as bonyl and ethoxycarbonyl_1-6Alkoxycar
Carbonyl, etc.), an optionally substituted carbamoyl group
(Eg, a 5- to 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl)
C, which may be substituted with dinyl, etc.)_1-6Alkyl group
Or acyl groups (eg formyl, C_2-6Alkanoyl, ba
Nzoyl, optionally halogenated C_1-6Arcoki
Sicarbonyl, optionally halogenated C_1-6Al
Substituted with (alkylsulfonyl, benzenesulfonyl, etc.)
Optional carbamoyl group, 1-azetidinyl carbonate
L, 1-pyrrolidinylcarbonyl, piperidinocarboni
L, morpholino carbonyl, 1-piperazinyl carbonyl
Etc.) and the like, and these optional substituents are
1 to 3 may be substituted at the substitutable position.

The "optionally substituted amino group", the "optionally substituted hydroxyl group" and the "optionally substituted amidino group" as the substituents of the above-mentioned "optionally substituted alkyl group". Is a "optionally substituted amino group", a "optionally substituted hydroxyl group" and a "substituted" as a substituent of the "optionally substituted aromatic homolog or heterocycle" described later. The same as the "optional amidino group" can be used.

Examples of the alkenyl group in the above-mentioned "optionally substituted alkenyl group" include vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 1
-Butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,
C _2-6 alkenyl such as 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like can be used. Here, as the substituent of the alkenyl, the same number of the same substituents as those in the above-mentioned “optionally substituted alkyl group” as the substituent can be used.

Examples of the alkynyl group in the above-mentioned "optionally substituted alkynyl group" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl. C _2-6 alkynyl such as 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl can be used. Here, as the substituent of the alkynyl group, the same number of substituents as those in the above-mentioned "optionally substituted alkyl group" as the substituent can be used.

As the aryl group in the "optionally substituted aryl group" as the substituent, for example, C _6-14 aryl such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like can be used. Here, as the substituent of the aryl group, the same number of substituents as those in the above-mentioned “optionally substituted alkyl group” as the substituent can be used.

The aralkyl group in the "optionally substituted aralkyl group" as the substituent is, for example, C _7-11 such as benzyl, phenethyl, naphthylmethyl and the like.
Aralkyl and the like can be used. Here, as the substituent of the aralkyl group, the same number of substituents as those in the above-mentioned "optionally substituted alkyl group" as the substituent can be used.

As the cycloalkyl group in the "optionally substituted cycloalkyl group" as the substituent, for example, C _3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like can be used. You can Here, as the substituent of the cycloalkyl group, the same number of substituents as those in the above-mentioned "optionally substituted alkyl group" as the substituent can be used.

As the cycloalkenyl group in the “optionally substituted cycloalkenyl group” as the above-mentioned substituent, for example, C _3-7 cycloalkenyl such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like are used. You can Here, as the substituent of the optionally substituted cycloalkenyl group, the same number of the same substituents as those in the above-mentioned "optionally substituted alkyl group" can be used. .

The heterocyclic group in the “optionally substituted heterocyclic group” as the substituent is, for example, an atom (ring atom) constituting the ring system selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like. Aromatic heterocyclic group containing at least 1 (preferably 1 to 4 and more preferably 1 to 2) of 1 to 3 (preferably 1 to 2) heteroatoms, saturated or unsaturated non-aromatic group Group heterocyclic groups (aliphatic heterocyclic groups) and the like can be used. Here, examples of the “aromatic heterocyclic group” include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,
2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,3-triazolyl,
5- to 6-membered monocyclic aromatic heterocyclic groups such as 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, and for example benzofuranyl, isobenzofuranyl, benzo [ b ].
Thienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl,
1,2-benzisoxazolyl, benzothiazolyl,
Benzopyranyl, 1,2-benzisothiazolyl, 1H
-Benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, buteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxadinyl. Nyl, thianthrenyl, phenatridinyl, phenatorolinyl, indoridinyl, pyrrolo [1,2- b ] pyridazinyl, pyrazolo [1,5- a ] pyridyl, imidazo [1,2- a ].
Pyridyl, imidazo [1,5- a ] pyridyl, imidazo [1,2- b ] pyridazinyl, imidazo [1,2- a ] pyrimidinyl, 1,2,4-triazolo [4,3- a ] pyridyl, 1, 8 to 12-membered condensed polycyclic aromatic heterocyclic group such as 2,4-triazolo [4,3- b ] pyridazinyl (preferably, the aforementioned 5- to 6-membered monocyclic aromatic heterocyclic group is benzene). A heterocyclic group condensed with a ring or a heterocyclic group in which two identical or different heterocycles of the above-mentioned 5 to 6-membered monocyclic aromatic heterocyclic group are condensed), more preferably the above-mentioned 5 to 6-membered A heterocyclic group in which a monocyclic aromatic heterocyclic group is condensed with a benzene ring, particularly preferably benzofuranyl,
Benzopyranyl, benzo [ b ] thienyl, etc.) and the like can be used.

As the "non-aromatic heterocyclic group", for example, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like 3-8 member ( Preferably 5 to 6 membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group), or 1,2,3,4-tetrahydroquinolyl, 1,2, Three and four
Using a non-aromatic heterocyclic group in which some or all of the double bonds are saturated in the above-mentioned monocyclic aromatic heterocyclic group or condensed polycyclic aromatic heterocyclic group such as tetrahydroisoquinolyl be able to. The substituent which the “optionally substituted heterocyclic group” as a substituent may have is a lower alkyl group (eg, C _1-6 such as methyl, ethyl, propyl and the like).
Alkyl, etc.), lower alkenyl groups (eg, C _2-6 alkenyl such as vinyl and allyl), lower alkynyl groups (eg, C _2-6 alkynyl such as ethynyl, propargyl, etc.), acyl groups (eg formyl, acetyl) , C _1-6 alkanoyl such as propionyl and pivaloyl, benzoyl etc.), an optionally substituted amino group, an optionally substituted hydroxyl group, a halogen atom (eg fluorine, chlorine, bromine, iodine etc., preferably chlorine, Bromine, etc.), an optionally substituted imidoyl group, an optionally substituted amidino group, etc. can be used. These optional substituents may be substituted at 1 to 5 (preferably 1 to 3) at substitutable positions. The “optionally substituted heterocyclic group” as the substituent may have “optionally substituted amino group”, “optionally substituted hydroxyl group”, “optionally substituted” The "imidoyl group" and the "optionally substituted amidino group" are the "optionally substituted amino group" as the substituent of the "optionally substituted aromatic homolog or heterocyclic group" described later. , The same as the "optionally substituted hydroxyl group", the "optionally substituted imidoyl group" and the "optionally substituted amidino group" can be used.

As the substituent, “may be substituted”
"Amino group", "optionally substituted imidoyl"
Group "," optionally substituted amidino group "," substituted "
Optionally substituted hydroxyl group ”,“ optionally substituted thiol ”
Examples of the substituent in the “aryl group” include halogen radicals.
Child (eg fluorine, chlorine, bromine, iodine, etc.), halogen
C which may be converted_1-6Alkoxy (eg Metoki
Ci, ethoxy, trifluoromethoxy, 2,2,2-to
Lifluoroethoxy, trichloromethoxy, 2,2,2
-Trichloroethoxy) and C_7-11Alkyl alley
Group (eg o-toluyl, m-toluyl, p-toluyl, chi
Silyl, mesityl, etc., preferably C_1-5Alkyl-pheny
Lower optionally substituted by a substituent selected from
Alkyl group (eg, methyl, ethyl, propyl, isopro
Pill, butyl, isobutyl, tert-butyl, pentyl,
C such as hexyl_1-6Alkyl, etc.), acyl group (C_1-6Al
Canoyl (eg formyl, acetyl, propionyl, pi
Valoyl, etc.), benzoyl, C _1-6Alkylsulfonyl
(Eg, methanesulfonyl, etc.), benzenesulfonyl
Etc.), optionally halogenated C_1-6Alkoxyca
Rubonyl group (eg, methoxycarbonyl, ethoxycarbo
Nyl, trifluoromethoxycarbonyl, 2,2,2-
Trifluoroethoxycarbonyl, trichloromethoxy
Carbonyl, 2,2,2-trichloroethoxy carbonyl
Etc.), C optionally substituted with a phenyl group _1-6Al
Coxycarbonyl group (eg, benzyloxycarbonyl
Etc.), aryl (eg, phenyl, 1-naphthyl, 2-na)
C such as futile_6-10Aryl, etc.), aralkyl (eg, Ben
C such as Jill and phenethyl_7-10Aralkyl, preferably
Phenyl-C _1-4Alkyl, etc.), arylalkenyl
(Example: C such as thinner mill_8-10Arylalkenyl, preferred
Phenyl-C_2-4Alkenyl etc.), heterocyclic group (previously
To the “optionally substituted heterocyclic group” as the substituent
Similar to the "heterocyclic group" in, preferably pyridinium
, More preferably 4-pyridyl etc.)
You can These optional substituents have 1 at the substitutable position.
Or 3 may be substituted.

The "amino group" in the "optionally substituted amino group" as the substituent is an optionally substituted imidoyl group (eg, C _1-6 alkylimidoyl (eg, formylimido). yl, acetyl imidoyl etc.), C _1-6 alkoxy imidoyl, C _1-6 alkyl thio imidoyl, amidino, etc.), with one to two C _1-6 alkyl amino group which may be substituted with a group such as It may be substituted. These optional substituents have 1 at the substitutable position.
Or two may be substituted. In addition, two substituents may combine with a nitrogen atom to form a cyclic amino group. In such a case, the cyclic amino group may be, for example, 1
-Azetidinyl, 1-pyrrolidinyl, piperidino, thiomorpholino, morpholino, 1-piperazinyl and lower alkyl at the 4-position (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl) Etc.), aralkyl (eg C _7-10 aralkyl such as benzyl and phenethyl), aryl (eg C _6-10 aryl such as phenyl, 1-naphthyl, 2-naphthyl etc.) and the like. 1-piperazinyl, 1-pyrrolyl, 1-imidazolyl and the like 3-8 member (preferably 5
~ 6-membered) cyclic amino and the like can be used.

The alkylsulfinyl group in the above-mentioned “optionally substituted alkylsulfinyl group” is methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, se
C _1-6 such as c-butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl and hexylsulfinyl
Alkylsulfinyl can be used. Here, as the substituent of alkylsulfinyl, the same number of substituents as the above-mentioned substituent in the “optionally substituted alkyl” can be used.

As the "optionally esterified or amidated carboxyl group" as the substituent,
Carboxyl groups, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, carbamoyl, N-monosubstituted carbamoyl and N, N-disubstituted carbamoyl can be used. Here, as the “alkoxycarbonyl”, for example, methoxycarbonyl,
C _1-6 alkoxycarbonyl such as ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl (lower Alkoxycarbonyl) and the like, among which C such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl can be used.
_1-3 alkoxycarbonyl and the like are preferable. The “lower alkoxycarbonyl” may have a substituent, and examples of the substituent include a hydroxyl group and an optionally substituted amino group [the amino group is, for example, 1 to 5 halogen atoms (eg, fluorine). , A lower alkyl group optionally substituted with chlorine, bromine, iodine, etc. (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc., preferably methyl, ethyl, etc.), an acyl group (eg formyl, acetyl, propionyl, C _1-6 alkanoyl pivaloyl, benzoyl, etc.), a carboxyl group, a one or two substituents such as C _{1 -6} alkoxycarbonyl You may have. ], A halogen atom (eg fluorine, chlorine, bromine, iodine etc.), a nitro group, a cyano group, 1 to 5 halogen atoms (eg fluorine, chlorine, bromine, iodine etc.)
A lower alkoxy group optionally substituted with (for example, methoxy, ethoxy, n-propoxy, isopropoxy, n
- butoxy, isobutoxy, sec- butoxy, C _1-6 alkoxy such as tert- butoxy, preferably methoxy,
Ethoxy etc.) and the like can be used. Further, these substituents are preferably the same or different and substituted by 1 or 2 to 3 (preferably 1 or 2).

Here, "aryloxycarbonyl"
For example, phenoxycarbonyl, 1-naphthoxyca
Lubonyl, 2-naphthoxycarbonyl, 1-phenanth
C such as oxycarbonyl_6-14Aryloxycarbonyl, etc.
Is preferred. The "aryloxycarbonyl" is a substituent
May have a substituent represented by the above-mentioned substituents.
With a substituent in "alkoxycarbonyl" as a group
A similar number of similar things can be used. here
Examples of the “aralkyloxycarbonyl” include benzene
Diloxycarbonyl, phenethyloxycarbonyl, etc.
C_7-14Aralkyloxycarbonyl and the like (preferably,
C_6-10Aryl-C_1-4Alkoxy-carbonyl etc.)
preferable. The "aralkyloxycarbonyl" is a substituent
May have a substituent represented by the above-mentioned substituents.
With a substituent in "alkoxycarbonyl" as a group
A similar number of similar things can be used. here
Examples of the "N-monosubstituted carbamoyl" include, for example, lower alkenyl.
Rutile (eg methyl, ethyl, propyl, isopropyl)
Ru, butyl, isobutyl, tert-butyl, pentyl,
C such as Kicil_1-6Alkyl, etc.), lower alkenyl (eg,
Vinyl, allyl, isopropenyl, propenyl, buteni
C such as le, pentenyl and hexenyl _2-6Alkenyl
Etc.), cycloalkyl (eg, cyclopropyl, cyclobu
C such as chill, cyclopentyl, cyclohexyl_3-6Shiku
Low alkyl etc.), aryl (eg phenyl, 1-naphthyl)
C such as le and 2-naphthyl_6-10Aryl etc.), aralkyl
(Eg C such as benzyl, phenethyl, etc._7-10Aralkyl, good
More preferably Phenyl-C_1-4Alkyl, etc.), arylal
Kenyl (eg C such as cinnamyl)_8-10Aryl alkeni
Preferably phenyl-C_2-4Alkenyl etc.), complex
A cyclic group (for example, "may be substituted" as the aforementioned substituent)
Same as "heterocyclic group" in "heterocyclic group", etc.
Can be used. The lower alkyl, lower alkene
Ru, cycloalkyl, aryl, aralkyl, aryl
The alkenyl and heterocyclic groups may have a substituent,
Examples of the substituent of are:
A similar number of substituents in "carbonyl"
Can be used.

Here, "N, N-disubstituted carbamoyl"
Means a carbamoyl group having two substituents on the nitrogen atom, and as one example of the substituent, the same substituent as the above-mentioned "N-monosubstituted carbamoyl" is used. And the other example is
For example, lower alkyl (eg, methyl, ethyl, propyl,
C _1-6 alkyl such as isopropyl, butyl, tert-butyl, pentyl, hexyl, etc., C _3-7 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C _7-10 aralkyl (eg, benzyl) , Phenethyl and the like, preferably phenyl-C _1-4 alkyl and the like) and the like can be used. Further, two substituents may combine with a nitrogen atom to form a cyclic amino, and examples of the cyclic aminocarbamoyl in such a case include 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, 1-piperazinylcarbonyl and 4-position a lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert- butyl, pentyl, C _{1 6} alkyl hexyl, etc.), 1-pipe that may have aralkyl (eg, C _7-10 aralkyl such as benzyl and phenethyl), aryl (eg, C _6-10 aryl such as phenyl, 1-naphthyl, 2-naphthyl, etc.) and the like A 3- to 8-membered (preferably 5- to 6-membered) cyclic aminocarbonyl such as radinylcarbonyl can be used.

The substituents of the "optionally substituted thiocarbamoyl group" and the "optionally substituted sulfamoyl group" as the above-mentioned substituents are "esterified or amidated" as the above-mentioned substituents. The same substituents as "N-monosubstituted carbamoyl" and "N, N-disubstituted carbamoyl" in the "good carboxyl group" can be used.

As the above-mentioned "acyl derived from sulfonic acid" as the substituent, for example, the above-mentioned "N-monosubstituted carbamoyl" having one substituent on the nitrogen atom and sulfonyl is bonded can be used. However, preferably, acyl such as C _1-6 alkylsulfonyl such as methanesulfonyl and ethanesulfonyl can be used.

As the "acyl derived from carboxylic acid" as a substituent, use is made of a hydrogen atom or the above-mentioned "N-monosubstituted carbamoyl" having one substituent on the nitrogen atom and a carbonyl bonded to each other. However, preferably, C _1-6 alkanoyl such as formyl, acetyl, propionyl and pivaloyl, and acyl such as benzoyl can be used.

R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or a substituent. Here, as the substituent, the same number of substituents as those of the above-mentioned "optionally substituted aromatic homolog or heterocycle" can be used. Preferably a lower alkoxy group (eg, C _1-6 alkoxy such as methoxy, ethoxy, propoxy, etc.),
Halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.),
Lower alkyl group (eg C such as methyl, ethyl, propyl, etc.
_1-6 alkyl etc.), lower alkenyl group (eg C _2-6 alkenyl such as vinyl, allyl etc.), lower alkynyl group (eg C _2-6 alkynyl such as ethynyl, propargyl etc.), even if substituted Good amino group, optionally substituted hydroxyl group, cyano group, optionally substituted amidino group, carboxy group, lower alkoxycarbonyl group (eg, C such as methoxycarbonyl and ethoxycarbonyl)
_1-6 alkoxycarbonyl etc.), C optionally substituted with an optionally substituted carbamoyl group (eg 5 to 6 membered monocyclic aromatic heterocyclic group (eg pyridinyl etc.)
_1-6 alkyl group or acyl group (eg, formyl, C _2-6 alkanoyl, benzoyl, optionally halogenated C _1-6 alkoxycarbonyl, optionally halogenated C _1-6 alkylsulfonyl, benzene A carbamoyl group optionally substituted with sulfonyl, etc.), 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, 1-piperazinylcarbonyl, etc.). Here, "an optionally substituted amino group", "an optionally substituted hydroxyl group", and "an optionally substituted amidino group"
As the "optionally substituted amino group", "optionally substituted hydroxyl group", and "substituted" as the above-mentioned "optionally substituted aromatic homocycle or heterocycle" The same as the "optional amidino group" can be used.

T and T'represent an oxygen atom or a formula NR (wherein R represents a hydrogen atom or a substituent). Here, when R represents a substituent, the same number of the same substituents as the above-mentioned "optionally substituted amino group" substituents can be used as this substituent. Preferably, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), an optionally halogenated C _1-6 alkoxy (eg, methoxy, ethoxy, trifluoromethoxy,
2,2,2-trifluoroethoxy, trichloromethoxy, 2,2,2-trichloroethoxy, etc.) and C _7-11
Alkylaryl groups (eg o-toluyl, m-toluyl,
p-toluyl, xylyl, mesityl, etc., preferably C _1-5
Lower alkyl group which may be substituted with a substituent selected from alkyl-phenyl etc. (eg methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl etc. C _1-6 alkyl) Etc.), acyl group (C _1-6 alkanoyl (eg, formyl, acetyl, propionyl, pivaloyl etc.), benzoyl, C
_1-6 alkylsulfonyl (eg, methanesulfonyl, etc.),
Benzenesulfonyl, etc.), an optionally halogenated C _1-6 alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl,
Trichloromethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.), a C _1-6 alkoxycarbonyl group optionally substituted by a phenyl group (eg, benzyloxycarbonyl etc.), aryl (eg, phenyl, 1-).
C _6-10 aryl such as naphthyl and 2-naphthyl), aralkyl (eg C _7-10 aralkyl such as benzyl and phenethyl, preferably phenyl-C _1-4 alkyl etc.), arylalkenyl (eg cinnamyl etc.) _C8-10 arylalkenyl, preferably phenyl- _C2-4 alkenyl, etc.),
Heterocyclic group (the same as the "heterocyclic group" in the "optionally substituted heterocyclic group" as the substituent, preferably pyridyl, more preferably 4-pyridyl and the like), or may be substituted. Imidoyl group (for example, C _1-6 alkylimidoyl (eg, formylimidoyl, acetylimidoyl, etc.), C _1-6 alkoxyimidoyl, C _1-6 alkylthioimidoyl, amidino, etc.), 1 to 2 groups C _1-6
An amino group which may be substituted with an alkyl group or the like can be used.

The transition metal catalyst is 3 to 11 in the periodic table.
A catalyst composed of a metal belonging to a group element is shown. Examples of the transition metal include ²¹ Sc to ²⁹ Cu, ³⁹ Y to ⁴⁷ Ag, ⁷² Hf to ⁷⁹ A.
u and the like can be used, and Pt, Pd, Ru and Rh are preferable. As a preferable transition metal catalyst, a zero-valent palladium catalyst, a zero-valent platinum catalyst, or the like can be used. As the zero-valent platinum catalyst, platinum black, a catalyst in which a zero-valent platinum metal is supported on a solid carrier (platinum carbon, platinum-alumina, etc.), and a zero-valent platinum metal complex (tetrakistriphenylphosphine platinum ( 0) etc. are used. Of these, platinum black and platinum carbon are preferable, and platinum carbon is particularly preferable. Examples of the zero-valent palladium catalyst include palladium black, a catalyst in which a zero-valent palladium metal is supported on a solid carrier (palladium carbon, palladium-silica gel, palladium-alumina, palladium-barium sulfate, etc.), and a zero-valent palladium metal. Complex of (tetrakistriphenylphosphine palladium
(0), bis (dibenzalacetone) dipalladium (0), etc. are used. Of these, palladium black and palladium carbon are preferable, and palladium carbon is particularly preferable.

The base includes an inorganic base and an organic base, and is not particularly limited as long as it is used in organic synthesis. Examples of the inorganic base include alkali metal hydrides such as lithium hydride, potassium hydride and sodium hydride; inorganic hydroxides such as lithium oxide, potassium hydroxide, sodium hydroxide and calcium hydroxide; sodium carbonate and carbonic acid. It is possible to use salts of carbonic acid such as potassium and sodium hydrogen carbonate. Examples of the organic base include lithium ethoxide, lithium tert-butoxide,
Metal alkoxides having 1 to 6 carbon atoms such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; metal phenoxides such as potassium phenoxide and sodium phenoxide; acetic acid salts such as sodium acetate and potassium acetate; n-butyl Organolithium salts such as lithium, t-butyllithium and diethylaminolithium;
Hydrazines such as phenylhydrazine and p-tolylhydrazine; amidines; quaternary ammonium hydroxides; sulfonium bases; amines and the like can be used. Preferred are metal alkoxides and amines.

The amine refers to a compound in which a hydrogen atom of ammonia is substituted with a hydrocarbon residue which may be substituted, such as an aliphatic amine which may be substituted and an aromatic amine which may be substituted. Is included. Here, "a compound substituted with an optionally substituted hydrocarbon residue",
The substituents in the "optionally substituted aliphatic amine" and the "optionally substituted aromatic amine" are the same as the substituents in the above-mentioned "optionally substituted aromatic homolog or heterocycle". Any number of similar ones can be used. The “aliphatic amine” specifically includes aliphatic primary amines such as methylamine, ethylamine, n-propylamine, isopropylamine, butylamine, amylamine, methanolamine, ethanolamine; dimethylamine, methylethylamine, diethylamine. , Ethylpropylamine, di (n-propyl) amine, ethylisopropylamine, diisopropylamine, methylbutylamine, dibutylamine, butylamylamine, diamylamine, N, N′-dibenzylethylenediamine,
Aliphatic secondary amines such as diethanolamine; trimethylamine, methyldiethylamine, triethylamine, methylethylpropylamine, methyldiethylamine, tri (n-propyl) amine, triisopropylamine, tri (n-butyl) amine, diisopropylethylamine, triamylamine , Aliphatic tertiary amines such as triethanolamine; aliphatic unsaturated amines such as allylamine, diallylamine, triallylamine; cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, cyclohexyldimethylamine,
Alicyclic amine such as dicyclohexylamine; pyrrolidine, N-methylpyrrolidine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, DBU
(1,8-diazabicyclo [5,4,0] undec-7-ene), DB
A cyclic amine such as N (1,5-diazabicyclo [4,3,0] none-5-ene) can be used. Preferred are amines having 1 to 3 substituents with C _1-6 aliphatic hydrocarbons.
“Aromatic amine” specifically includes, for example, aniline, methylaniline, N, N-dimethylaniline, ethylaniline, N, N-diethylaniline, o-toluidine, m-toluidine, p-toluidine, benzylamine, Dibenzylamine, tribenzylamine, diphenylamine, triphenylamine, α-naphthylamine, β-naphthylamine, pyridine, picoline, quinoline, quinazoline, lutidine, γ-collidine, 4-dimethylaminopyridine and the like can be used, and preferably Examples thereof include amines having 1 to 3 substituents with a C ₆ aromatic hydrocarbon group and amines having 1 to 3 substituents with a C _7-14 aralkyl group or a C _7-14 alkylaryl group.

In the present invention, the salt is, for example, a salt with an inorganic base, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, etc. You can Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt and the like. Preferable examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like. it can. Suitable examples of salts with inorganic acids include hydrochloric acid, hydrobromic acid,
A salt with nitric acid, sulfuric acid, phosphoric acid or the like can be used. Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p. -A salt with toluenesulfonic acid or the like can be used. Suitable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Can be used.

In the present invention, the general formula (I)

[Chemical 27] [In the formula, each symbol has the same meaning as described above. ] The compound represented by general formula (II)

[Chemical 28] [In the formula, each symbol has the same meaning as described above. ] When T of a compound (I) is an oxygen atom, the compound (II) whose T'is an oxygen atom is obtained, and T of a compound (I) is represented by formula NR (Wherein each symbol has the same meaning as defined above), T'is also represented by the formula N
A compound (II) having a group represented by -R (in the formula, each symbol has the same meaning as defined above) is obtained.

In the present invention, the general formula (I)

[Chemical 29] [In the formula, each symbol has the same meaning as described above. ] The compound represented by the general formula (I
I)

[Chemical 30] [In the formula, each symbol has the same meaning as described above. ] In the case of producing a compound represented by the following or a salt thereof, when T of the compound (I) is an oxygen atom and the amine used in the reaction is a primary amine, T'is represented by the formula NR (in the formula, The symbol has the same meaning as described above.), A compound (II) which is a group represented by the formula (1) is obtained, and T of the compound (I) is represented by the formula NR (wherein each symbol has the same meaning as described above). When it is a group represented by the formula (II), a compound (II) which is a group represented by the formula NR (wherein each symbol has the same meaning as described above) may be obtained.

A compound of the general formula (X) which is a compound of the present invention

[Chemical 31] [In the formula, T represents an oxygen atom or a group represented by the formula NR (in the formula, R represents a hydrogen atom or a substituent), and R ¹ ,
R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and represent a hydrogen atom or a substituent. However, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and
At least one group of R ⁶ is a halogen atom. ]
Or a salt thereof, and a general formula (XI)

[0050]

[Chemical 32] [In the formula, each symbol has the same meaning as described above. ] When T represents an oxygen atom, the compound or its salt represented by the general formula (X ')

[0051]

[Chemical 33] [In the formula, each symbol has the same meaning as described above. ] The compound or its salt represented by these, and general formula (XI ')

[0052]

[Chemical 34] [In the formula, each symbol has the same meaning as described above. ] When it represents a compound represented by the formula or a salt thereof, and T represents the formula NR (wherein R has the same meaning as described above), each represents a general formula (X ″).

[0053]

[Chemical 35] [In the formula, each symbol has the same meaning as described above. ] The compound or its salt represented by this, and general formula (XI '')

[0054]

[Chemical 36] [In the formula, each symbol has the same meaning as described above. ] It represents the compound represented by this, or its salt. These general formulas (X) and (X
I) [or a compound represented by the general formula (X ′), (X ″), (XI ′) and (XI ″)] or a salt thereof is a solvate or an unsolvate, particularly a hydrate. It may be a substance or a non-hydrate. When these compounds exist as configurational isomers (configurational isomers), diastereomers, conformers, etc., each can be isolated by known separation and purification means, if desired, and When these compounds are racemic, they can be separated into S-form and R-form by ordinary optical resolution means. In the case where these compounds have stereoisomers, the present invention includes single isomers and a mixture thereof, and these compounds are isotopes (eg, ³ H, ¹⁴ C). , ³⁵ S) and the like.

Preferred examples of R include C _1-6 alkyl groups such as methyl group, ethyl group and isopropyl group;
Hydroxy C _1-6 alkyl group such as hydroxymethyl group, hydroxyethyl group and hydroxyisopropyl group; halogeno C _1-6 alkyl substituted with 1 to 3 halogen atoms such as fluoromethyl, trifluoromethyl and trifluoroethyl Group; mercapto C _1-6 alkyl group such as mercaptomethyl group, mercaptoethyl group, mercapto-t-butyl group; 4-piperidyl C _1-6 alkyl group such as 4-piperidylmethyl group, 4-piperidylethyl group; toluyl , A benzyl group which may have a substituent such as xylyl, mesityl, 4-methoxybenzyl group, 3-ethoxy-4-methoxybenzyl group and the like can be used. R ¹ , R ² ,
Preferable groups of R ³ , R ⁴ , R ⁵ and R ⁶ are, for example, the same or different, a hydrogen atom; a halogen atom such as a chlorine atom and a bromine atom; a cyano group; an acetyl group; a hydroxyl group; a mercapto group; a carboxyl group. Group; C _1-6 alkyl group such as methyl, ethyl, isopropyl, butyl, pentyl, hexyl; methoxy, ethoxy, isopropoxy, butoxy,
A C _1-6 alkoxy group such as pentoxy and hexoxy; a C _2-6 alkenyl group such as vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl; an amino group; a carbamoyl group; a sulfamoyl group and the like can be used. Preferred examples of ring A include, for example, benzene, naphthalene,
C _6-14 aryl such as anthracene and phenanthrene,
For example, furan, thiophene, pyrrole, oxazole,
5- to 6-membered monocyclic aromatic heterocycles such as thiazole, imidazole, 1,2,4-thiadiazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, and benzofuran, 8 to 8 such as isobenzofuran, benzo [ b ] thiophene, indoline, isoindoline, 1H-indazole, benzindazole and benzoxazole.
A 12-membered condensed polycyclic aromatic heterocycle or the like can be used. Preferable examples of the transition metal catalyst include platinum black, platinum carbon, platinum (II) chloride, palladium black, palladium carbon, palladium (II) acetate, and palladium (II) chloride. Preferred examples of the base include, for example, methylamine, ethylamine, triethylamine, and other C _1-6 aliphatic hydrocarbon 1 to 3 substituted amines, sodium methoxide, sodium ethoxide, potassium tert-butoxide, and the like. A metal alkoxide having 1 to 6 carbon atoms or the like can be used.

[0056]

BEST MODE FOR CARRYING OUT THE INVENTION Next, the general method for carrying out the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

The compound of the present invention can be produced by appropriately using a known organic chemical synthesis method, but preferably, it can be efficiently produced by the following method of the present invention. [Production method A-1]

[Chemical 37]

[Wherein each symbol has the same meaning as defined above and R ^E
Is a group forming an ester with a carboxylic acid (eg, an _optionally substituted aryl group such as a C _1-6 alkyl group, a C _7-16 aralkyl group, a C _7-16 alkylaryl group), and a base is a base, H ⁺ represents an acid, respectively. [Step (a-1) → (a-2)] The compound (a-1) can be obtained by reacting the compound (a-1) with an alcohol in the presence of a strong acid catalyst to esterify the compound (a-2). As the strong acid catalyst used in this reaction,
Mineral acids such as sulfuric acid and hydrogen chloride, organic acids such as methanesulfonic acid and p-toluenesulfonic acid, and strongly acidic ion exchange resins are used. Among them, mineral acids such as sulfuric acid and hydrogen chloride are preferable, and sulfuric acid is particularly preferable. The amount of sulfuric acid used in this reaction is 0.02 to 2 times by weight, preferably 0.05 to 0.5 times by weight based on the starting compound (a-1). The amount of alcohol used is 0.2 to 20 times by weight with respect to the raw material compound (a-1), preferably 0.5.
~ 5 times by weight. The reaction temperature is 50 ° C to 200 ° C, preferably 60 ° C to 150 ° C. The reaction time is about 5 minutes to 20 hours.

[Step (a-2) → (a-4)] The compound (a-2) is reacted with an oxalic acid diester in the presence of a base to convert the compound to an oxalacetic acid derivative, and then the compound is closed by an acid to give a compound ( a-4)
Can be obtained. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene and xylene, and aliphatic hydrocarbons such as hexane, pentane and heptane. , Esters such as ethyl acetate and butyl acetate, ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether and tetrahydrofuran, aliphatic halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane, methanol, ethanol, 1- Propanol, 2-propanol, 1-butanol, 2-butanol, 2-
Examples thereof include alcohols such as methyl-1-propanol, and among them, the above alcohols, esters, ethers and aromatic hydrocarbons are preferable, and particularly methanol, ethanol, 2-propanol, ethyl acetate, tetrahydrofuran and toluene are preferable. preferable. These may be used alone or as a mixture of two or more kinds at an appropriate ratio. The amount of the solvent used in this reaction is 1 to 50 times by weight, preferably 2 to 25 times by weight, particularly preferably 2 to 10 times by weight, of the starting compound (a-2). As the base used in this reaction,
Alkali metal hydrides such as potassium hydride and sodium hydride, such as lithium ethoxide and lithium-
C1-C6 metal alkoxides such as tert-butoxide, sodium methoxide, sodium ethoxide, carboxyl-tert-butoxide, such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, hydrogen carbonate. Inorganic bases such as sodium, for example, triethylamine, tri (n-propyl) amine, tri (n-butyl) amine, diisopropylethylamine, cyclohexyldimethylamine, pyridine,
Lutidine, γ-collidine, N, N-dimethylaniline,
Tertiary amines such as N-methylpiperidine, N-methylpyrrolidine and N-methylmorpholine are used. Above all, it is preferable to use alkali metal hydrides and metal alkoxides. The amount of these bases used depends on the amount of the raw material compound (a
It is a 1- to 10-fold molar quantity versus -2), preferably a 1- to 5-fold molar quantity, and particularly preferably a 1-2-fold molar quantity. The amount of oxalic acid diester used in this reaction is 1 with respect to the starting compound (a-2).
~ 10 times mol, preferably 1 to 5 times mol, particularly preferably 1
~ 2 times the molar amount. The reaction temperature for conversion into an oxalacetic acid derivative is usually 0 to 200 ° C, preferably 50 to 150 ° C, and the reaction time is usually 5 minutes to 20 hours. Examples of the acid used in this reaction include mineral acids such as sulfuric acid and hydrogen chloride, organic acids such as methanesulfonic acid and p-toluenesulfonic acid, and strongly acidic ion exchange resins. Among them, mineral acids and organic acids are preferable. . The amount of these acids used is 1 to 50 times by weight, preferably 2 to 20 times by weight based on the starting compound (a-2). The reaction temperature for the ring closure reaction is usually 0 to 200 ° C., preferably 50 to 150.
℃. The reaction time is usually about 5 minutes to 20 hours.

[Step (a-4) → (a-5)] and [Step (a-6) → (a
-7)] When the compound (a-4) or the compound (a-6) is reacted with an amine, the acid anhydride is converted into an imide to obtain the compound (a-5) or the compound (a-7). . The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene and xylene, and aliphatic hydrocarbons such as hexane, pentane and heptane. , Esters such as ethyl acetate and butyl acetate, diethyl ether, diisopropyl ether, t-
Butylmethyl ether, ethers such as tetrahydrofuran, methylene chloride, chloroform, aliphatic halogen hydrocarbons such as dichloroethane, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol,
Alcohols such as 2-butanol and 2-methyl-1-propanol, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpiperidone, dimethyl sulfoxide, hexamethylphosphoric amide, dimethylimidazolidi Examples thereof include organic acids such as non-formic acid, formic acid and acetic acid, water and the like, and among them, the above alcohols, organic acids and water are preferable. These may be used alone or as a mixture of two or more kinds at an appropriate ratio. The amount of solvent used in this reaction is 5 to 50 times by weight relative to compound (a-4) or compound (a-6),
It is preferably 5 to 30 times by weight, and particularly preferably 5 to 20 times by weight. The amount of amine used in this reaction is 1 to 50 times mol, preferably 1 to 20 times mol, of the starting compound (a-4) or the starting compound (a-6). Reaction temperature is usually 0 ~
200 ℃, preferably 50 ~ 150 ℃, more preferably 80
To 150 ° C, more preferably 100 to 140 ° C, and even more preferably 120 to 130 ° C. The reaction time is usually about 5 minutes to 20 hours.

[Step (a-4) → (a-6)] and [Step (a-5) → (a
-7)] 1) When the compound (a-4) or the compound (a-5) is dehydrogenated with a transition metal catalyst, the compound (a-6) or the compound (a-7) can be obtained. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, for example, benzene, toluene, xylene, cumene, naphthalene,
Aromatic hydrocarbons such as quinoline, hexane, pentane,
Aliphatic hydrocarbons such as heptane and decalin, esters such as ethyl acetate and butyl acetate, ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether and tetrahydrofuran, aliphatic halogens such as methylene chloride, chloroform and dichloroethane. Hydrocarbons, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-
Alcohols such as propanol, N, N-dimethylformamide, N, N-dimethylacetamide, amides such as N-methylpiperidone, dimethyl sulfoxide, hexamethylphosphoric amide, dimethylimidazolidinone, formic acid,
Examples thereof include organic acids such as acetic acid, water and the like. Among them, the above alcohols and organic acids are preferable, and acetic acid is more preferable. These may be used alone or as a mixture of two or more kinds at an appropriate ratio. The amount of the solvent used in this reaction is 5 to 100 times by weight, preferably 5 to 50 times by weight that of the compound (a-4) or the compound (a-5). Examples of the transition metal catalyst used in this reaction include a platinum catalyst, a palladium catalyst, a rhodium catalyst, a ruthenium catalyst and the like, and among them, a platinum catalyst and a palladium catalyst are preferable. The amount of these transition metal catalysts used depends on the starting compound (a-4) or starting compound.
The amount is 0.05 to 5 times mol, preferably 0.1 to 2 times mol, of (a-5). The reaction temperature is usually 0 to 200 ° C, preferably 50 to 150
℃, more preferably 80 ~ 150 ℃, more preferably 100 ~ 140 ℃, even more preferably 120 ~ 130 ℃
Is. The reaction time is usually about 5 minutes to 20 hours. 2) Compound (a-6) or compound (a-7) can be obtained by subjecting compound (a-4) or compound (a-5) to a dehydrogenation reaction with a base. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene and xylene,
Hexane, pentane, heptane and other aliphatic hydrocarbons,
Esters such as ethyl acetate and butyl acetate, ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether and tetrahydrofuran, aliphatic halogen hydrocarbons such as methylene chloride, chloroform and dichloroethane, methanol, ethanol, 1-propanol , 2-propanol, 1-butanol, 2-butanol, 2-
Alcohols such as methyl-1-propanol, N, N-dimethylformamide, N, N-dimethylacetamide, amides such as N-methylpiperidone, dimethyl sulfoxide, hexamethylphosphoramide, dimethylimidazolidinone, formic acid, acetic acid, etc. Examples of the organic acids, water, and the like, and among them, the above alcohols, organic acids, and water are preferable. These may be used alone or as a mixture of two or more kinds at an appropriate ratio. The amount of the solvent used in this reaction is 5 to 100 times by weight, preferably 5 to 100 times the amount of the compound (a-4) or the compound (a-5).
50 times the weight. The amount of base used in this reaction is
1 to 3 with respect to the raw material compound (a-4) or the raw material compound (a-5)
00 times mol, preferably 1 to 200 times mol, more preferably 2 times
˜200 times mol, more preferably 10 to 200 times mol, and even more preferably 20 to 100 times mol. The base used in the reaction is not particularly limited, and metal alkoxides such as sodium ethoxide and potassium ethoxide; metal hydrides such as sodium hydride; aliphatic amines such as methylamine and aromatic amines such as benzylamine; Further, it may be a primary amine, secondary amine or tertiary amine. The reaction temperature is usually 0 to 200 ° C, preferably 50 to 150
℃, more preferably 80 ~ 150 ℃, more preferably 100 ~ 140 ℃, even more preferably 120 ~ 130 ℃
Is. The reaction time is usually about 1 to 100 hours.
In particular, when the solvent is acetic acid and amine is used as the base, the molar ratio of amine to acetic acid in the solvent (acetic acid / amine) is preferably 0.01 to 6.0, more preferably 0.1.
To 5.5, more preferably 1 to 5, and even more preferably 1 to 4.

[Step (a-4) → (a-7)] When the compound (a-4) is reacted with an excess amount of amine, the acid anhydride is converted into an imide and, at the same time, dehydrogenation proceeds, The compound (a-7) can be obtained. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, for example, benzene,
Aromatic hydrocarbons such as toluene and xylene, hexane,
Aliphatic hydrocarbons such as pentane and heptane, esters such as ethyl acetate and butyl acetate, ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether and tetrahydrofuran, aliphatic halogens such as methylene chloride, chloroform and dichloroethane. Hydrocarbons, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-
Alcohols such as propanol, N, N-dimethylformamide, N, N-dimethylacetamide, amides such as N-methylpiperidone, dimethyl sulfoxide, hexamethylphosphoric amide, dimethylimidazolidinone, formic acid,
Examples thereof include organic acids such as acetic acid, water and the like, and among them, the above alcohols, organic acids and water are preferable. These may be used alone or as a mixture of two or more kinds at an appropriate ratio. The amount of the solvent used in this reaction is the compound (a-4) or the compound (a-
It is 5 to 100 times by weight, preferably 5 to 50 times by weight, as compared with 6). The amount of amine used in this reaction depends on the starting compound
(a-4) or 1 to 300 times mol to the starting compound (a-6),
It is preferably 1 to 200 times mol, more preferably 2 to 200 times mol, still more preferably 10 to 200 times mol, and even more preferably 20 to 100 times mol. Reaction temperature is usually 0-200
℃, preferably 50 ~ 150 ℃, more preferably 80 ~ 1
The temperature is 50 ° C, more preferably 100 to 140 ° C, and even more preferably 120 to 130 ° C. The reaction time is usually about 1 to 100 hours. Particularly when the solvent is acetic acid, the molar ratio of amine to acetic acid in the solvent (acetic acid / amine) is preferably 0.01 to 6.0, more preferably 0.1 to 5.5, further preferably 1 to 5, and even more preferably Is 1 to 4.

[Production Method A-2]

[Chemical 38]

[In the formula, each symbol has the same meaning as described above. [Step (a-1 ′) → (a-2 ′)] can be performed according to the above [Step (a-1) → (a-2)] . [Step (a-3 ′) → (a-4 ′)] is as described above.
It can be performed according to [Step (a-2) → (a-4)] . [Process
(a-4 ′) → (a-5 ′)] and [step (a-6 ′) → (a-7 ′)] are the same as the above [step (a-4) → (a-5)] and [step (a-6) → (a-7)] . [Step (a-4 ') → (a-6')] and
[Step (a-5 ′) → (a-7 ′)] is the same as the above [Step (a-4) → (a-6)]
And [step (a-5) → (a-7)] . [Engineering
Step (a-4 ′) → (a-7 ′)] can be carried out according to the above-mentioned [Step (a-4) → (a-7)] .

[Step (a-2 ′) → (a-3 ′)] Compound (a-2 ′) is subjected to Sandmeyer reaction (after conversion of aromatic primary amine to diazonium salt with nitrous acid, copper halide is used). (I) synthesis of aromatic halide)
(a-3 ') can be obtained. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene and xylene, and aliphatic hydrocarbons such as hexane, pentane and heptane. , Esters such as ethyl acetate and butyl acetate, ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether and tetrahydrofuran, aliphatic halogen hydrocarbons such as methylene chloride, chloroform and dichloroethane , Methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-
Examples thereof include alcohols such as methyl-1-propanol, water and the like, and above all, the above ketones and water are preferable. These may be used alone or as a mixture of two or more kinds at an appropriate ratio.
The amount of solvent used in this reaction is 5 to 100 times by weight, preferably 5 to 30 times by weight based on the compound (a-2 ′). As the acid used in the conversion reaction to the diazonium salt, mineral acids such as sulfuric acid, hydrobromic acid, hydrogen chloride, etc., organic acids such as acetic acid, methanesulfonic acid, etc. are used, and among these, mineral acids are preferred. The amount of these acids used is 5 to 100 times by weight, preferably 5 to 30 times by weight based on the starting compound (a-2 ′).
The amount of sodium nitrite used is 1 to 5 times mol, preferably 1 to 2 times mol, of the starting compound (a-2 ′). The reaction temperature is generally -20 to 20 ° C, preferably -10 to 10 ° C. The reaction time is usually about 5 minutes to 1 hour. As the copper compound used in the conversion reaction to a halide, copper (I) chloride,
Monovalent copper such as copper (I) bromide or copper (I) iodide is used. The amount used is 1 to 5 times mol, preferably 1 to 2 times mol, of the starting compound (a-2 ′). The reaction temperature is usually 0 to 50 ° C,
It is preferably 0 to 30 ° C. The reaction time is usually about 5 minutes to 20 hours.

[Production Method B-1]

[Chemical Formula 39]

[In the formula, each symbol has the same meaning as described above. [Step (b-1) → (b-2)] can be performed according to the above-mentioned [Step (a-1) → (a-2)] . [Step (b-2) → (b-4)] is the same as the above [Step (a-
2) → (a-4)] . [Process (b-4) → (b
-5)] and [step (b-6) → (b-7)] are the same as the above [step (a-4) → (a-
5)] and [step (a-6) → (a-7)] . [Step (b-4) → (b-6)] and [Step (b-5) → (b-7)] are the same as the above [Step (a-4) → (a-6)] and [Step (a -5) → (a-7)] [Step (b-4) → (b-7)] is the same as the above [Step
(a-4) → (a-7)] .

[Production Method B-2]

[Chemical 40]

[In the formula, each symbol has the same meaning as described above. ] [Step (b-1 ′) → (b-2 ′)] is the same as the above [Step (a-1 ′) → (a-2 ′)]
It can be performed according to. [Step (b-2 ′) → (b-3 ′)] can be performed according to the above [Step (a-2 ′) → (a-3 ′)] . [Step (b-3 ′) → (b-4 ′)] is the same as the above [Step (a-3 ′) → (a-
4 ')] . [Process (b-4 ') → (b-
5 ')] and [step (b-6') → (b-7 ')] are the same as those in the above [step (a-
4 ′) → (a-5 ′)] and [step (a-6 ′) → (a-7 ′)] . [Process (b-4 ') → (b-6')]
Step (b-5 ') → (b-7')] is the same as the above [Step (a-4 ') → (a-6')].
And [Step (a-5 ′) → (a-7 ′)] . [Step (b-4 ′) → (b-7 ′)] is the same as the above [Step (a-4 ′) → (a-
7 ')] .

The compound (a-
1), (a-1 '), (b-1), and (b-1') are produced by commonly known organic chemical synthesis methods or by the Journal of the American Chemical Society (J. Am. Chem.
Soc.), Vol. 58, p. 2314, 1936 or a method similar thereto. The compound obtained in each of the above steps is a means known per se from the reaction mixture,
For example, it may be isolated and purified by using means such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin layer chromatography, etc., or the reaction mixture as it is may be provided as a raw material for the next step. You can also do it.
When the compound is obtained in a free state by each reaction of the present invention, it may be converted into a salt according to a conventional method, and when it is obtained as a salt, it is converted into a free form or other salt according to a conventional method. You can also do it.

The salt of the compound can be produced according to a method known per se, for example, by adding an inorganic acid or an organic acid to the compound. When a compound may have stereoisomers, all of these individual isomers and mixtures thereof are naturally included in the scope of the present invention, and these isomers can be individually produced if desired. Further, the compound or a salt thereof may be a hydrate,
Both hydrates and non-hydrates are included within the scope of the present invention.

The method of the present invention and the compound of the present invention are useful as intermediates for the production of pharmaceuticals, agricultural chemicals, and many general-purpose chemicals. Some examples are shown below. 1) For example, by reacting the compound (b-4) with H ₂ NCH ₂ CH ₂ OH to synthesize the following compound useful for the production of the photocrosslinkable polymer described in JP-A-59-104360. You can

[Chemical 41]

2) For example, by reacting (b-4) with H ₂ NCH ₂ CH ₂ SH, the following compound used for producing an electronic circuit described in JP-A-58-196208 can be synthesized. it can.

[Chemical 42]

3) For example, by reacting (b-4 ′) with RNH ₂ and then reacting with copper (I) cyanide or the like, WO932
The following compounds useful as tranquilizers and neuroleptic agents described in the 2310 publication can be synthesized.

[Chemical 43]

4) For example, after lithiation of (b-6 ') with BuLi, it is reacted with CO ₂ to lead to a carboxylic acid and esterified to give a dental adhesive described in JP-A-60-202873. The following compounds useful as agents can be synthesized.

[Chemical 44]

5) For example, by reacting (b-7) with RNH ₂ , the following compounds useful as antitumor agents, antiarthritic agents and therapeutic agents for septic shock described in WO0025777 can be synthesized. .

[Chemical formula 45]

Further, the formula (XII)

[Chemical formula 46] For the production of a compound having a partial structure represented by the general formula (XIII)

[Chemical 47]

[In the formula, each symbol has the same meaning as described above. ]
The compound represented by or a salt thereof can be effectively used. As described above, the compound of the present invention and the production method of the present invention are very useful as intermediates for producing pharmaceuticals, agricultural chemicals, or many general-purpose chemicals, and production methods thereof.

[0079]

EXAMPLES The present invention will be described in more detail below with reference to Production Examples, Examples and Reference Examples, but the present invention is not limited thereto.

[0080]

[Chemical 48]

Reference Example 1 4.31 g (20 mmol) of 4- (3-aminophenyl) butyric acid was added to ethanol.
Suspended in 10 mL. Add 0.4 mL of concentrated sulfuric acid and add 1 at 100 ° C
Reflux for hours. 20 mL of ethyl acetate and 40 mL of 1N sodium hydroxide were added to the reaction solution to separate it. The organic layer was washed successively with 30 mL of 1N sodium hydroxide and 30 mL of water. The organic layer was concentrated under reduced pressure, ethyl acetate was added, and the concentration was repeated. The residue was dried under reduced pressure to obtain 3.93 g (yield 94.7%) of ethyl 4- (3-aminophenyl) butyrate as a light brown liquid. ¹ H-NMR (300MHz, CDCl ₃ ): δ 1.27 (t, 3H), 1.95 (quint,
2H), 2.33 (t, 2H), 2.58 (t, 2H), 3.63 (brs, 2H), 4.1
4 (q, 2H), 6.53-6.61 (m, 3H), 7.06-7.11 (m, 1H).

Reference Example 2 To 207 mg (1 mmol) of ethyl 4- (3-aminophenyl) butyrate, 1 mL of 48% hydrobromic acid was added. Sodium nitrite under ice cooling 69mg
A 0.5 mL solution of (1 mmol) in water was added dropwise. The generated diazonium salt solution was added dropwise to a mixed solution of 143 mg (1 mmol) of copper (I) bromide, 48% hydrobromic acid (0.2 mL) and acetone (2 mL). 1 at room temperature
After stirring for an hour, add 6 mL of ethyl acetate and 4 mL of water to the reaction mixture under ice cooling.
Was added to separate the layers. Organic layer 1N sodium hydroxide 4mL ×
2, washed sequentially with 4 mL of water x 2. The organic layer is concentrated under reduced pressure,
Ethyl acetate was added and concentration was repeated. The residue was dried under reduced pressure to give ethyl 4- (3-bromophenyl) butyrate as an orange oil.
210 mg (yield 77.5%) was obtained. ¹ H-NMR (300MHz, CDCl ₃ ): δ 1.26 (t, 3H), 1.94 (quint,
2H), 2.31 (t, 2H), 2.63 (t, 2H), 4.13 (q, 2H), 7.09-
7.18 (m, 2H), 7.32-7.34 (m, 2H).

Example 1 61 mg (0.9 mmol) of sodium ethoxide was suspended in 1 mL of THF. Add diethyl oxalate 105 mg (0.72 mmol) and ethyl 4- (3-bromophenyl) butyrate 163 mg (0.6 mmol), and bath
Refluxed at 100 ° C for 1 hour. Under ice cooling, 4% of 80% sulfuric acid was added, and the mixture was stirred at room temperature for 1.5 hours and then at 80 ° C for 30 minutes. The precipitated crystals were collected by filtration and washed 3 times with 2 mL of water. After drying under reduced pressure, pale yellow crystalline 7-bromo-4,5-dihydronaphtho [1,2-c] furan-
110 mg of 1,3-dione (yield 65.9%) was obtained. ¹ H-NMR (300MHz, CDCl ₃ ): δ 2.79 (t, 2H), 3.09 (t, 2
H), 7.46 (s, 1H), 7.50 (dd, 1H), 7.93 (d, 1H).

[0084]Example 2 420 mg (10.5 mmol) of sodium hydride (60%) was suspended in 7 mL of THF.
Made cloudy. Diethyl oxalate 1.23g (8.4mmol), 4- (3-butane)
Add 1.95 g (7 mmol) of ethyl lomophenyl) butyrate, and add 80
The mixture was stirred at ° C for 2 hours. The reaction solution was concentrated under reduced pressure. methane
Sulfonic acid (7 mL) was added, and the mixture was stirred at 80 ° C for 1 hr. Anti
After cooling the reaction solution, the precipitated crystals were collected by filtration and washed with 2 mL of ethanol.
And washed twice with 2 mL of water. Dried under reduced pressure, yellow
Crystalline 7-bromo-4,5-dihydronaphtho [1,2-c] furan-1,3
-1.15 g of dione (yield 59.0%) was obtained. ¹ H-NMR (300MHz, CDCl₃): δ 2.79 (t, 2H), 3.09 (t, 2
H), 7.46 (s, 1H), 7.50 (dd, 1H), 7.93 (d, 1H).

Example 3 84 mg (0.3 mmol) of 7-bromo-4,5-dihydronaphtho [1,2-c] furan-1,3-dione was suspended in 1 mL of acetic acid. 40% under ice cooling
Add 0.23 mL (3 mmol) of methylamine (methanol solution),
The external bath was stirred at 80 ° C for 5 hours. After cooling to room temperature, the precipitated crystals were collected by filtration and washed with 0.5 mL of methanol three times. After drying under reduced pressure, yellow crystals of 7-bromo-2-methyl-4,5-dihydro-1
H-benzo [e] isoindole-1,3 (2H) -dione 68 mg (yield
77.3%). ¹ H-NMR (300MHz, CDCl ₃ ): δ 2.68 (t, 2H), 2.99 (t, 2
H), 3.06 (s, 3H), 7.39 (s, 1H), 7.43 (dd, 1H), 7.98
(d, 1H).

Example 4 28 mg (0.1 mmol) of 7-bromo-4,5-dihydronaphtho [1,2-c] furan-1,3-dione was suspended in 1 mL of acetic acid. 10% Pd-C (50
% wet) 112 mg was added, and the mixture was refluxed at 120 ° C for 6 hours. Pd-C
Was filtered and washed with ethyl acetate. The filtered solution was concentrated under reduced pressure to obtain 22 mg (yield 78.6%) of white crystals of 7-bromonaphtho [1,2-c] furan-1,3-dione. ¹ H-NMR (300MHz, DMSO-d ₆ ): δ 8.08 (dd, 1H), 8.09 (d,
1H), 8.52 (d, 1H), 8.59 (d, 1H), 8.63 (d, 1H).

Example 5 29 mg (0.1 mmol) of 7-bromo-2-methyl-4,5-dihydro-1H-benzo [e] isoindole-1,3 (2H) -dione was suspended in 1 mL of acetic acid. . 116% of 10% Pd-C (50% wet) was added, and the outside bath was 120 ℃.
Reflux for 10 hours. Pd-C was filtered and washed with ethyl acetate. The filtered solution was concentrated under reduced pressure to give white crystals of 7-bromo-2-
Methyl-1H-benzo [e] isoindole-1,3 (2H) -dione 2
2 mg (yield 75.9%) was obtained. ¹ H-NMR (300MHz, DMSO-d ₆ ): δ 3.08 (s, 3H), 7.92 (d, 1
H), 7.94 (dd, 1H), 8.34 (d, 1H), 8.48 (d, 1H), 8.68
(d, 1H).

Example 6 223 mg (0.8 mmol) of 7-bromo-4,5-dihydronaphtho [1,2-c] furan-1,3-dione was suspended in 8 mL of acetic acid. 40% under ice cooling
Add 3.1 mL (40 mmol) of methylamine (methanol solution),
The external bath was stirred at 120 ° C for 48 hours. After concentrating the reaction solution, the precipitated crystals were collected by filtration. The crystals were washed 3 times with 2 mL of methanol.
After drying under reduced pressure, pale yellow crystals of 7-bromo-2-methyl-1H-
Benzo [e] isoindole-1,3 (2H) -dione 145 mg (yield 6
2.5%). ¹ H-NMR (300MHz, DMSO-d ₆ ): δ 3.08 (s, 3H), 7.92 (d, 1
H), 7.94 (dd, 1H), 8.34 (d, 1H), 8.48 (d, 1H), 8.68
(d, 1H). Elemental analysis value: C ₁₃ H ₈ NO ₂ Br ・ 0.4H ₂ O Actual value C, 52.60 H, 2.94 N, 4.67 Calculated value C, 52.52 H, 2.98 N, 4.71

Reference Example 3

[Chemical 49]

300 mg (7.5 mmol) of sodium hydride (60%)
It was suspended in 7.5 mL of THF. Diethyl oxalate 877mg (6mmo
l), ethyl 4- (4-methoxyphenyl) butyrate 1.11 g (5 mmol)
Was added, and the mixture was stirred at 80 ° C for 1.5 hours. The reaction solution was concentrated under reduced pressure. Add 7.5 mL of methanesulfonic acid, and add 1 at the outside bath at 80 ℃.
Stir for hours. After cooling the reaction solution, the precipitated crystals were collected by filtration and washed successively with 6 mL of ethanol twice and 6 mL of water twice. Dried under reduced pressure, yellow crystalline 8-methoxy-4,5-dihydronaphtho
873 mg (yield 75.9%) of [1,2-c] furan-1,3-dione was obtained. ¹ H-NMR (300MHz, CDCl ₃ ): δ 2.76 (t, 2H), 3.02 (t, 2
H), 3.85 (s, 3H), 6.95 (dd, 1H), 7.19 (d, 1H), 7.61
(d, 1H).

Reference Example 4

[Chemical 50]

60 mg (1.5 mmol) of sodium hydride (60%) was added to T
It was suspended in 1 mL of HF. Diethyl oxalate 175 mg (1.2 mmo
l), 192 mg (1 mmol) of ethyl 4-phenylbutyrate were added, and the external bath was 8
The mixture was stirred at 0 ° C for 1.5 hours. The reaction solution was concentrated under reduced pressure. Methanesulfonic acid (1 mL) was added, and the mixture was stirred at 80 ° C for 1.5 hours. The external bath was stirred at 120 ° C for 1 hour. After cooling the reaction solution, the precipitated crystals were collected by filtration and washed successively with 1 mL of ethanol twice and 1 mL of water twice. After drying under reduced pressure, 110 mg (yield 55.0%) of 4,5-dihydronaphtho [1,2-c] furan-1,3-dione as white crystals was obtained. ¹ H-NMR (300MHz, CDCl ₃ ): δ 2.79 (t, 2H), 3.10 (t, 2
H), 7.26-7.45 (m, 3H), 8.06 (dd, 1H).

Example 7

[Chemical 51]

60 mg (0.3 mmol) of 4,5-dihydronaphtho [1,2-c] furan-1,3-dione was suspended in 3 mL of acetic acid. Under ice cooling 40
1.2 mL (15 mmol) of methylamine (methanol solution) was added, and the mixture was stirred at 120 ° C for 48 hours in the outer bath. After concentrating the reaction solution, the precipitated crystals were collected by filtration. The crystals were washed 3 times with 1 mL of methanol. After drying under reduced pressure, 2-methyl-1H-benzo as pale yellow crystals
45 mg (yield 71.4%) of [e] isoindole-1,3 (2H) -dione was obtained. ¹ H-NMR (300MHz, CDCl ₃ ): δ 3.23 (s, 3H), 7.62-7.75
(m, 2H), 7.86 (d, 1H), 7.95 (d, 1H), 8.16 (d, 1H), 8.
94 (d, 1H).

[0095]

As described above, according to the production method of the present invention, it is possible to obtain a condensed aromatic compound which is useful as an intermediate for the production of pharmaceuticals, agricultural chemicals, or many general-purpose chemicals. The production method can be carried out under mild and safe conditions and is useful as an industrial production method.

Claims (18)

[Claims] 1. A compound represented by the general formula (I): [In the formula, T represents an oxygen atom or a group represented by the formula NR (wherein R represents a hydrogen atom or a substituent), R ¹ and R ² are the same or different, and are a hydrogen atom or a substituent. Represents a group, and Ring A represents an optionally substituted aromatic homocycle or heterocycle. ] The compound represented by the formula or a salt thereof is subjected to a dehydrogenation reaction in the presence of 1) a transition metal catalyst or 2) a base. [In the formula, each symbol has the same meaning as defined above, and T ′ represents an oxygen atom or a group represented by the formula NR (wherein R represents a hydrogen atom or a substituent). ] The manufacturing method of the compound or its salt represented by these. 2. The method according to claim 1, wherein the transition metal catalyst is a zero-valent palladium catalyst or a zero-valent platinum catalyst. 3. The method according to claim 2, wherein the zero-valent palladium catalyst or the zero-valent platinum catalyst is a catalyst supported on a solid carrier. 4. The base is 1) an alkali metal hydride, 2)
The production method according to claim 1, wherein the base is one selected from an inorganic hydroxide, 3) a metal alkoxide having 1 to 6 carbon atoms, and 4) an amine or a salt thereof. 5. The amine is an aliphatic amine.
The manufacturing method described. 6. The aliphatic amine is used in an amount of 1 to 200 times by mole with respect to the compound of the general formula (I).
The manufacturing method described. 7. A compound represented by the general formula (V): [In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom or a substituent, and Ring A represents an optionally substituted aromatic homocycle or heterocycle. ] The compound or its salt represented by the following general formula (VI): [In the formula, R represents a hydrogen atom or a substituent. ] The compound represented by the general formula (VII) characterized by reacting with an amine compound represented by [In the formula, each symbol has the same meaning as described above. ] The manufacturing method of the compound or its salt represented by these. 8. The method according to claim 1, wherein the reaction is carried out at about 0 ° C. to about 200 ° C. 9. The method according to claim 1, wherein acetic acid is used as a solvent. 10. The method according to claim 9, wherein the molar ratio of amine to acetic acid as a solvent (acetic acid / amine) is 0.01 to 6. 11. A compound represented by the general formula (III): [In the formula, T represents an oxygen atom or a group represented by the formula NR (in the formula, R represents a hydrogen atom or a substituent), and R ¹ ,
R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and represent a hydrogen atom or a substituent. ] The compound represented by the formula or a salt thereof is subjected to a dehydrogenation reaction in the presence of 1) a transition metal catalyst or 2) a base to give a compound represented by the general formula (IV): [In the formula, each symbol has the same meaning as defined above, and T ′ represents an oxygen atom or a group represented by the formula NR (wherein R represents a hydrogen atom or a substituent). ] The manufacturing method of Claim 1 which obtains the compound or its salt represented by this. 12. A compound represented by the general formula (VIII): [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or a substituent. ] The compound or its salt represented by the following general formula (VI) [In the formula, R represents a hydrogen atom or a substituent. ] The compound represented by the general formula (IX): [In the formula, each symbol has the same meaning as described above. ] The manufacturing method of Claim 7 which obtains the compound or its salt represented by this. 13. The method according to claim 11 or 12, wherein R ¹ , R ² , R ³ , R ⁴ , and R ⁶ are hydrogen atoms, R ⁵ is a halogen atom, and R is a C _1-6 alkyl group. The manufacturing method described. 14. A compound represented by the general formula (X): [In the formula, T represents an oxygen atom or a group represented by the formula NR (in the formula, R represents a hydrogen atom or a substituent), and R ¹ ,
R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and represent a hydrogen atom or a substituent. However, at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is a halogen atom. ] The compound or its salt represented by these. 15. A compound represented by the general formula (XI): [In the formula, T represents an oxygen atom or a group represented by the formula NR (in the formula, R represents a hydrogen atom or a substituent), and R ¹ ,
R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and represent a hydrogen atom or a substituent. However, at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is a halogen atom. ] The compound or its salt represented by these. 16. The compound according to claim 14 or 15, wherein R ⁵ is a halogen atom. 17. The compound according to claim 16, wherein R ¹ , R ² , R ³ , R ⁴ , and R ⁶ are hydrogen atoms and R is a C _1-6 alkyl group. 18. Formula (XII): Use of the compound according to claim 15 for the preparation of a compound having a partial structure represented by: